WO2001039782A1 - Agent de radioprotection - Google Patents
Agent de radioprotection Download PDFInfo
- Publication number
- WO2001039782A1 WO2001039782A1 PCT/JP2000/008423 JP0008423W WO0139782A1 WO 2001039782 A1 WO2001039782 A1 WO 2001039782A1 JP 0008423 W JP0008423 W JP 0008423W WO 0139782 A1 WO0139782 A1 WO 0139782A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- radiation
- lactic acid
- polylactic acid
- reaction
- condensation
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to a radiation protective agent having a protective function against radiation damage in a living body. More specifically, the present invention relates to a radiation protective agent comprising, as an active ingredient, a polylactic acid mixture having a degree of condensation within a certain range.
- vitamin E is a viscous oil that is insoluble in water because it has a long-chain hydrocarbon group (fityl group) in its molecule. For this reason, when administering biminmin E for the purpose of preventing free radical damage to the living body, there was a disadvantage that it could not be used in the form of a solution such as an oral solution or an injection.
- An object of the present invention is to provide a radiation protective agent having an action of protecting radiation and having no harmful side effects, and a food or drink using the same.
- the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, administered a cyclic and / or linear polylactic acid mixture having a condensation degree of 3 to 19 to mice before irradiation with radiation. By doing so, it was found that the mouse could be protected from radiation, and the present invention was completed.
- a cyclic and / or linear poly-L-lactic acid mixture having a degree of condensation of 3 to 19 has been known as an antineoplastic agent (Japanese Patent Application Laid-Open No. Hei 9-222 7388 and As a QOL improving agent for cancer patients (Japanese Patent Application No. 11-398984; Japanese Journal of Cancer Therapy, Vol. 33, No. 3, No. 3) 49 3) It is reported to be useful.
- the cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 19 has a hypoglycemic effect and is useful as a drug for preventing and / or treating diabetes or diabetic complications. (Japanese Patent Application No.
- a radiation protective agent comprising, as an active ingredient, a cyclic and / or linear polylactic acid mixture having a degree of condensation of 3 to 19.
- the radioprotective agent of the present invention is used, for example, for the prevention and / or treatment of radiation therapy disorders.
- the lactic acid, a repeating unit in the polylactic acid consists essentially of L-lactic acid.
- a cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 19 is obtained by subjecting lactic acid to dehydration condensation under an inert atmosphere, and removing the ethanol and methanol soluble components of the resulting reaction solution.
- eluting with an aqueous solution of 25 to 50% by weight of acetonitrile at pH 2-3 and then eluting with an aqueous solution of at least 90% by weight of acetonitrile at pH 2-3. is there.
- the dehydration condensation is performed under a nitrogen gas atmosphere by stepwise reduction in pressure and temperature.
- the reverse phase column chromatography is performed by ODS column chromatography.
- a food and drink for radiation protection comprising a cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 19 as an active ingredient.
- Preferred embodiments of the polylactic acid mixture used in the food and drink of the present invention are as described above.
- a cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 19 in the production of a radioprotective agent or a food or drink for radioprotection.
- a method for protecting radiation comprising a step of administering an effective amount of a cyclic and / or linear polylactic acid mixture having a degree of condensation of 3 to 19 to mammals including humans.
- FIG. 1 shows a mass spectrum of the polylactic acid mixture obtained in Production Example 1 of the present specification.
- FIG. 2 is a graph showing the survival rate of C 3 H / HeN mice (control group) after whole body irradiation.
- FIG. 3 is a graph showing the survival rate of C 3 H / HeN mice (CPL administration group) after whole body irradiation.
- FIG. 4 is a graph showing mortality on day 30 after whole body irradiation of C 3 H / HeN mice. Open circles indicate the control group, and black circles indicate the CPL-administered group.
- the term "radioprotectant” refers to an agent for protecting cells or organisms from the adverse effects on cells caused by radiation exposure.
- the radioprotectant of the present invention is used to protect cells from harmful cell damage caused by radiation exposure.
- Radiation is high-energy radiation, such as X-rays and gamma rays, that have the effect of creating ion pairs in a substance. Exposure to radiation is normal if it occurs as a result of environmental radiation, such as from a nuclear explosion, radioactive material leakage, access to radioactive materials, etc. And can occur as a result of radiation therapy, such as radiation therapy for various tumors.
- Adverse effects on the above-mentioned cells include damage to cellular DNA, such as DNA chain cleavage, disruption of cell function, cell death and induction of tumors.
- Radiation damage is an acute injury that occurs in tissues where cells are constantly undergoing renewal (mucous membranes such as skin, oral cavity, small intestine, and vagina), and a chronic injury that occurs in cells or tissues that undergo slow or no renewal. Classified as disability. Chronic disorders also include physical and genetic disorders.
- Examples of radiation disorders include radiation gastritis, radiation necrosis, radiation ulcer, radiation burn, radiation hepatitis, radiation stomatitis, radiation osteonecrosis, radiation syndrome (radiation sickness), radiation epithelitis , Radiation esophagitis, radiation nephritis, radiation myelopathy, radiation fibrosis, radiation proctitis, radiation mucositis, radiation pneumonia, radiation cataract, radiation keratitis, radiation leukopenia Disease, radiation dermatitis, radiation anemia, radiation cystitis, radiation leukemia, and the like, but are not limited thereto.
- the radioprotective agent of the present invention can be used for treatment and prevention of such damages due to radiation exposure.
- the radioprotective agent of the present invention can be used as an adjuvant to radiation therapy for the prevention and / or treatment of radiation therapy disorders.
- radiation exposure to radiation therapy to treat tumors, which kills cancer cells also has a detrimental cellular effect on radiation in normal cells.
- the agents of the present invention can protect cells from harmful cellular effects by preventing or eliminating or reducing the degree of these harmful effects of radiation.
- radiotherapy includes, for example, radiotherapy for tumors.
- tumors include acute lymphoblastic, acute myeloid, chronic lymphocytic, and acute myoblast.
- Leukemias such as malignant and chronic myocyte leukemia; cancers of the cervix, esophagus, stomach, knee, breast, ovary, small intestine, colon and lung; osteosarcoma, lipoma, liposarcoma, hemangiomas and hemangiosarcomas
- Sarcomas such as; non-melaninous and melaninous melanoma; and carcinosarcoma, lymphoid histology, vesicular reticulum, cell sarcoma, Hodgkin's disease, and non-Hodgkin's phosphorus
- Examples include, but are not limited to, mixed tumors such as papillomas.
- a cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 19 is used as an active ingredient.
- the “polylactic acid mixture” referred to in the present invention means a mixture in which cyclic and / or linear polylactic acid having a condensation degree of 3 to 19 is present in an arbitrary ratio. That is, the term “mixture” means a mixture of polylactic acids having any of the condensation degrees of 3 to 19, and is also used as a concept including a mixture of cyclic and linear polylactic acids. . Such a “polylactic acid mixture” can be obtained by dehydrating and condensing lactic acid and purifying it by an appropriate method, as described later in this specification. In this specification, the term “polylactic acid mixture” is used for convenience, but includes a single component such as cyclic polylactic acid having a certain degree of condensation or chain polylactic acid having a certain degree of condensation. And polylactic acid consisting of
- the degree of condensation means the number of lactic acid units which are repeating units in polylactic acid.
- this lactic acid includes all of L-lactic acid, D-lactic acid or a mixture of these in any proportion.
- the lactic acid consists essentially of L-lactic acid.
- “substantially” means that the ratio of L-lactic acid units in the polylactic acid mixture [that is, (L—number of lactic acid units / L—number of lactic acid units + D—number of lactic acid units) X 100]
- it means 70% or more, preferably 80% or more, more preferably 85% or more, further preferably 90% or more, and particularly preferably 95% or more.
- the ratio of L-lactic acid units in the polylactic acid mixture The rate depends on the ratio of L-lactic acid and D-lactic acid present in the lactic acid used as starting material.
- the method for producing a cyclic and / or chain-like polylactic acid mixture having a degree of condensation of 3 to 19 is not particularly limited.
- Japanese Patent Application Laid-Open Nos. Japanese Patent Application No. 0-130153, Japanese Patent Application No. 11-139894 (the contents of these patent specifications are all incorporated herein by reference). Can be obtained by the production method described in (1).
- a cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 19 can be obtained by the following method A.
- lactic acid preferably lactic acid consisting essentially of L-lactic acid
- an inert atmosphere examples include a nitrogen gas and an argon gas, and it is preferable to use a nitrogen gas.
- the dehydration / condensation reaction is carried out at a temperature of 110 to 210 ° C, preferably 130 to 190 ° C, under reduced pressure of normal pressure to about 1 mmHg. It is particularly preferable to carry out the heating stepwise.
- the reaction time can be appropriately set. For example, the reaction can be performed for 1 to 20 hours.
- stepwise decompression and stepwise heating are used, the reaction time is divided into two or more partial reaction times, and the reaction is performed by setting the pressure and temperature in each part.
- the pressure can be reduced, for example, from normal pressure to 150 mmHg ⁇ 3 mmHg, and when stepwise heating is used, for example, 144 ° C ⁇ 15.5 ° C ⁇ 1 85 ° C.
- reaction can be carried out for 3 hours and 1.5 mm at 3 mmHg at 185 ° C.
- ethanol and methanol were added to the reaction mixture obtained by the dehydration condensation reaction, and the mixture was filtered and the filtrate was dried to obtain ethanol and methanol soluble components.
- the term “ethanol- and methanol-soluble matter” as used herein means a fraction soluble in a mixture of ethanol and methanol.
- the reaction mixture of the dehydration condensation reaction is mixed with ethanol and methanol, and the ratio of ethanol to methanol can be set as appropriate.
- ethanol: methanol 1: 9.
- the order and method of adding ethanol and methanol to the reaction mixture are not limited, and may be appropriately selected. For example, ethanol is first added to the reaction mixture for the dehydration condensation reaction, and then methanol is added. Can be added.
- the ethanol / methanol-soluble matter obtained above is subjected to reverse phase column chromatography, particularly chromatography using an octyl decylsilane (ODS) column.
- ODS octyl decylsilane
- the fraction eluted with an aqueous solution of acetonitrile is removed, and then the fraction eluted with an aqueous solution of acetonitrile having a pH of not less than 90% by weight of pH 2 to 3, preferably at least 99% by weight of an aqueous solution of acetonitrile is collected.
- a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 20 is obtained.
- the cyclic, Z- or chain-like polylactic acid mixture obtained as described above is neutralized with an alkali substance such as sodium hydroxide, dried under reduced pressure, and then formulated into a desired form as described below by a conventional method.
- an alkali substance such as sodium hydroxide
- Method B As another method for producing a cyclic and Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 19 used in the present invention, for example, the method described in Japanese Patent Application No. 11-265657 is described. (Method B) or the method described in Japanese Patent Application No. 11-265723 (Method C) can be used (described in these patent specifications). Are all incorporated herein by reference.) Hereinafter, Method B and Method C will be specifically described. Method B:
- lactide (3,6-dimethyl-1,4-dioxane-1,2,5-dione) is converted to RYM e (where R is an aliphatic group, an aromatic group, a substituted or unsubstituted silyl group, Or a lactic acid amide group (— CH (CH 3 ) CONH 2 group, Y represents an oxygen atom, a zeo atom, or NR ′, where R ′ represents a hydrogen atom, an aliphatic group or an aromatic group.
- Me is a method for producing a cyclic lactate oligomer by polymerizing in the presence of an alkali metal compound represented by the following formula:
- the aliphatic hydrocarbon group may be any of linear, branched, cyclic, or a combination thereof, and may be saturated or unsaturated, and has 1 to 12, preferably 1 carbon atoms. ⁇ 6.
- Examples of the aliphatic hydrocarbon group include linear (including both linear and branched) alkyl groups such as methyl, ethyl, propyl, butyl, octyl, and dodecyl; and cycloalkyl groups (for example, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.).
- the aromatic hydrocarbon group may have a substituent such as an alkyl group and includes a aryl group and an arylalkyl group, and has 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. It is.
- the aryl group which may have a substituent such as an alkyl group include phenyl, tolyl, and naphthyl.
- the arylalkyl group include benzyl, phenethyl, and naphthylmethyl.
- Examples of the substituent in the substituted or unsubstituted silyl group include an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
- Specific examples of the substituted silyl group include a trimethylsilyl group, a triphenylsilyl group, And a monobutyldimethylsilyl group.
- Examples of the alkali metal represented by Me include lithium, sodium, and potassium, and lithium is preferable.
- the RYMe metal compound represented by RYMe is obtained by adding R ′ — YH (where R ′ represents an aliphatic hydrocarbon group or an aromatic hydrocarbon group, and Y represents oxygen) to an alkyl alkali metal such as n-butyllithium. (Indicating an atom or an iodine atom).
- an alcohol compound or a thiol compound represented by R′—YH is dissolved in a suitable solvent (eg, anhydrous tetrahydrofuran or anhydrous dimethyl ether).
- a suitable solvent eg, anhydrous tetrahydrofuran or anhydrous dimethyl ether.
- the reaction can be carried out by adding an equivalent amount of an alkali metal alkyl such as n-butyllithium to a solution dissolved in an ether solvent or the like) and stirring the mixture.
- the reaction may be performed at a low temperature (for example, -78 ° C) for several minutes to 1 hour.
- a cyclic lactic acid oligomer can be produced by adding a lactide solution in a suitable solvent (eg, anhydrous tetrahydrofuran) to the reaction mixture containing the above-mentioned metal compound and stirring the mixture. .
- a suitable solvent eg, anhydrous tetrahydrofuran
- the used amount of the alkali metal compound (RYM e) and lactide is about 1: 1 to 1:10, preferably about 1: 2 to 1: 5, for example, 1: 3 or 1: 4. .
- the reaction temperature is between ⁇ 78 ° C. and room temperature.
- the reaction is preferably started at a temperature of 178 ° C. and gradually raised to room temperature.
- the reaction pressure is not particularly limited, and is preferably normal pressure.
- this reaction is preferably carried out in the presence of a solvent.
- a solvent inert to the reaction is preferable, and for example, an ether-based solvent (anhydrous tetrahydrofuran or anhydrous ethyl ether) or the like can be used.
- the reaction is preferably performed in an atmosphere of an inert gas such as nitrogen gas or argon gas.
- the composition of the lactic acid oligomer obtained as described above (that is, the mixing ratio of the cyclic lactic acid oligomer and the chain lactic acid oligomer) varies depending on the alkali metal compound used as a reaction aid.
- Alkali metal compounds having 1 to 3 carbon atoms (ROM e) (where R represents an alkyl group having 1 to 3 carbon atoms and Me represents an alkali metal)
- ROM e Alkali metal compounds having 1 to 3 carbon atoms
- R represents an alkyl group having 1 to 3 carbon atoms
- Me represents an alkali metal
- an alkali metal compound such as a lithium compound of an alkyl alcohol having 4 or more carbon atoms such as t-butyl alcohol or a thiophenol compound is used.
- an alkali metal compound such as a lithium compound of an alkyl alcohol having 4 or more carbon atoms such as t-butyl alcohol or a thiophenol compound.
- substantially only a cyclic lactic acid oligomer can be selectively obtained.
- the degree of polymerization of the lactic acid oligomer used in the present invention is from 3 to 19, preferably from 3 to 17.
- the degree of polymerization varies depending on the type of alkali metal compound used, the reaction temperature, and the reaction time.
- a mixture of cyclic (and possibly chain) lactic acid oligomers having different degrees of polymerization is present. It is conceivable that.
- a mixture composed of lactic acid oligomers having different degrees of polymerization can be used.
- means suitable for separating compounds having different molecular weights from the above-mentioned reaction mixture containing lactic acid oligomers having different degrees of polymerization for example, gel filtration) , HPLC, etc.
- a single lactic acid oligomer having a certain degree of polymerization may be purified and used.
- an alkali metal compound of a lactic acid amide (particularly, a lithium compound) (that is, a compound in which R is —CH (CH 3 ) CONH 2 group) is used as the alkali metal compound.
- This method comprises the steps of (i) heating lactic acid to a temperature in the range of 120 to 140 ° C under a pressure condition of 350 to 40 OmmHg to cause a dehydration-condensation reaction.
- reaction product is heated to a temperature of 150 to 160 ° C., and the reaction pressure is reduced to 0.5 to OmmHg at a rate of 0.5 to LmmHg / min.
- the pressure was reduced, only by-product water was distilled off while avoiding the distillation of lactide.
- the reaction was further performed under the same pressure conditions and reaction temperature of 150 to 160 ° C.
- lactic acid is heated under reduced pressure to cause a dehydrocondensation reaction.
- the reaction time in this case is 3 to 12 hours, preferably 5 to 6 hours.
- by-product water generated by dehydration-condensation of lactic acid is distilled off so that the reaction proceeds smoothly.
- lactide which is a dehydration-condensate of two molecules of lactic acid is removed. Carry out so as not to evaporate.
- the reaction pressure is reduced, preferably 300 to 500 mmHg, more preferably 350 to 400 mmHg, and under this pressure condition, the reaction pressure is in the range of 100 to 140 ° C, preferably 130 to 140 ° C. It is good to heat.
- the reaction in the first heating step mainly produces a reaction product mainly composed of a dehydration condensate of 3 to 23 molecules of lactic acid.
- a temperature higher than the reaction temperature in the first heating step preferably 145 to 180, so as to obtain an oligomer having an increased average degree of polymerization.
- C. more preferably 150 to 160.degree. C.
- the reaction pressure is lowered to a pressure of 10 to 50 mmHg, preferably 15 to 20 mmHg, and the dehydration condensation reaction is further continued.
- This reaction is also carried out under the same conditions as in the case of the reaction in the first heating step, in which by-product water is distilled off to make the reaction proceed smoothly, but lactide is not distilled off.
- the rate at which the reaction pressure is reduced to a pressure within the above range is 0.25 to 5 mmHg / min, preferably 0.5 to prevent lactide distillation and increase the reaction efficiency. It is usually necessary to keep it in the range of ⁇ 1 mmHg / min.
- the pressure reduction rate is lower than the above range, the time required to reduce the pressure to the predetermined pressure becomes longer, which is not preferable.On the other hand, when the pressure reduction rate is higher than the above range, the lactide is distilled off together with the by-product water. Is not preferred.
- the reaction is continued at this reaction pressure.
- the heating time in this case is 3 to 12 hours, preferably 5 to 6 hours.
- an lactic acid oligomer having an average degree of polymerization of 3 to 30, preferably 3 to 23 is obtained.
- the ratio of the cyclic oligomer in the oligomer is usually It is about 70 to 80% by weight.
- the reaction pressure is maintained at 0.25 to 5 mmHg, preferably 0.5 to 1 mmHg, and the reaction pressure is set to 144 to: L80 ° C.
- the reaction is further continued, preferably at a temperature of 150 to 160 ° C.
- the reaction time is 3 to 12 hours, preferably 5 to 6 hours.
- the by-product water generated in this case is also distilled off. In this case, it is preferable to avoid the distillation of lactide, but since the reaction product contains almost no lactide, it is not necessary to reduce the pressure-reducing rate significantly.
- lactic acid oligomer having an average degree of polymerization of 3 to 30, preferably 3 to 23, and having a cyclic oligomer content of 90% by weight or more, preferably 99% by weight or more is produced. Is done.
- the formulation of the radioprotective agent of the present invention is not particularly limited, and an appropriate formulation most suitable for the purpose of treatment or prevention can be selected from a formulation for oral administration or parenteral administration.
- Pharmaceutical forms suitable for oral administration include, for example, tablets, capsules, powders, granules, fine granules, syrups, solutions, emulsions, suspensions, chewables and the like.
- Formulations suitable for oral administration include, for example, injections (subcutaneous injection, intramuscular injection, intravenous injection, etc.), drops, inhalants, sprays, suppositories, gels, ointments and the like. Examples thereof include, but are not limited to, a transdermal absorbent in the form of a skin absorbent, a transmucosal absorbent, a patch or a tape.
- the dosage form is suitable for oral administration.
- Liquid preparations suitable for oral administration include water, sucrose, sorbitol, fructose, and other sugars; glycols such as polyethylene glycol and propylene glycol; sesame oil, olive oil, and soybean oil. Oils, p— It can be produced using preservatives such as hydroxybenzoic acid esters and flavors such as strawberry flavor and peppermint.
- excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, magnesium stearate, Lubricants such as talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin can be used.
- Formulations for injection or infusion suitable for parenteral administration preferably contain the above-mentioned substances, which are the active ingredient, dissolved or suspended in a sterile aqueous medium isotonic with the blood of the recipient.
- a solution can be prepared using a saline solution, a glucose solution, or an aqueous medium composed of a mixture of saline and a glucose solution.
- Formulations for enteral administration can be prepared using carriers such as cocoa butter, hydrogenated fats, or hydrogenated carboxylic acids, and are provided as suppositories.
- the above-mentioned substance as an active ingredient can be dispersed as fine particles, which does not irritate the oral and respiratory mucosa of the recipient and facilitates the absorption of the active ingredient.
- the body can be used.
- Specific examples of the carrier include lactose and glycerin.
- Formulations in the form of an aerosol or a dry pad can be prepared depending on the substance as the active ingredient and the properties of the carrier used. These preparations for parenteral administration include one or more selected from glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, and the like. Two or more auxiliary components can be added.
- the dose and the number of doses of the radioprotectant of the present invention are determined by the type of radiation to be protected, the amount of radiation, the condition or severity of the disease to be treated, the mode of administration, and the conditions such as the age and weight of the patient. Although it can be appropriately set depending on various factors, generally, the dose of the active ingredient is 20 to 200 mg / kg per day, preferably 20 to 20 mg / kg, more preferably Is 50 to 15 O mg / kg. It is preferable to administer the above dose of the drug in about 1 to 4 times a day, preferably about 2 to 4 times a day. When the radiation protective agent of the present invention is used for radiation protection, radiation irradiation
- the radioprotectant of the present invention can be administered to any mammal, including humans, but is preferably administered to humans.
- the cyclic, Z- or chain-like polylactic acid mixture having a condensation degree of 3 to 19 used in the present invention is used not only as a radiation protective agent but also as a food additive or as a food additive. It can also be added to foods such as health foods.
- Specific examples of the food and drink products according to the present invention containing a cyclic and / or chain polylactic acid mixture having a condensation degree of 3 to 19 include soft drinks, drinks, health foods, specified health foods, and functional foods.
- Health foods or supplements including beverages, commonly referred to as functionally active foods, dietary supplements, supplements, feeds, feed additives, and the like.
- polylactic acid mixture examples include, for example, sweets such as chewing gum, chocolate, candy, tablet confectionery, jelly, cookie, biscuit, and yogurt, and ice confectionery such as ice cream and ice confectionery.
- sweets such as chewing gum, chocolate, candy, tablet confectionery, jelly, cookie, biscuit, and yogurt
- ice confectionery such as ice cream and ice confectionery.
- Beverages including juice, coffee, cocoa, etc.
- nutritional drinks including juice, coffee, cocoa, etc.
- nutritional drinks including juice, coffee, cocoa, etc.
- beauty drinks etc.
- bread bread
- ham soups
- jams spaghetti
- frozen foods etc.
- the polylactic acid mixture used in the present invention can be added to seasonings, food additives and the like, and used.
- the food and drink of the present invention encompasses all forms of food and drink such as health food and supplementary food, and the type thereof is not particularly limited.
- a mixture of a cyclic and / or chain polylactic acid having a degree of condensation of 3 to 19 to various oral or enteral nutritional supplements, beverages, and the like can be provided as foods and drinks.
- the composition of such foods and drinks includes, in addition to the cyclic and / or chain polylactic acid mixture having a degree of condensation of 3 to 19, proteins, lipids, sugars, vitamins and / or vitamins. Neurals and the like can be included.
- the form of the food or drink is not particularly limited, and may be any of solid, powder, liquid, gel, and slurry forms as long as it is easy to ingest.
- the content of the polylactic acid mixture in the food or drink is not particularly limited, but is generally about 0.1 to 20% by weight, more preferably about 0.1 to 10% by weight.
- the amount of the polylactic acid mixture contained in the food or drink is preferably contained to such an extent that the object of the present invention can be achieved, preferably from about 0.1 lg to about 10 g, more preferably from about 0.1 g to 1 ingested food or drink. ⁇ Approximately 5 g to 3 g.
- Production Example 1 Production of polylactic acid mixture
- the obtained polylactic acid was kept at 100 ° C, and after adding 10 Oml of ethanol and 40 Oml of methanol, the mixture was allowed to cool. This was added to 50 Oml of methanol, stirred well, allowed to stand, and then purified by filtration. The filtrate was dried under reduced pressure and dissolved in acetate nitrile to make a total volume of 200 ml (stock solution).
- mice 8- to 11-week-old female C 3 H / HeLa mice were housed in acryl cases and bred.
- the mice consisted of a control group fed freely with the standard solid diet CE2 (obtained from CLEA Japan) and 0.1% by weight (the fraction obtained by chromatography in Production Example 1 was used as it was, The group was divided into a CPL group in which a standard solid meal CE2 containing a polylactic acid mixture (hereinafter, also referred to as CPL) having a concentration of 0.1% by weight was freely taken and bred. After the start of CPL administration, the whole body was irradiated with 4 to 8 Gy of X-rays on the 55th day.
- CPL polylactic acid mixture
- mice in the control group and the CPL group survived under irradiation of 4 to 7 Gy.
- the mortality rate of the control group was 55.6% (5/9)
- the mortality rate of the CPL-administered group was 11.1% (1/9).
- mice were bred in the same manner as in Test Example 1, and were irradiated with whole body irradiation of 7.5 to 9.5 Gy on the 58th day after the start of CPL administration.
- the LD 50/30 was 8.03 (7.85 to 8.20) Gy in the control group, and 13.70 (13.37 to: 14.03) Gy in the CPL administration group.
- Test example 3
- the same dose (7.5 to 8.5 Gy) was applied to the whole body of the control group and the CPL administration group (CPL administration period: irradiation 13 before the experiment was completed). After irradiation, mice were observed over time and the number of surviving mice was recorded. The results are shown in Figs. From the results of FIGS. 2 and 3, it can be seen that the CPL-administered group (FIG. 3) has a higher survival rate than the control group (FIG. 2). As shown in FIG. 4, the LD 50/30 was 7.57 (7.44 to 7.71) Gy in the control group, and 8.00 (7.91 to 8) in the CPL administration group. 09) It was Gy. From these results, it was demonstrated that when CPL administration was started before irradiation, radioprotective effects were exhibited.
- the radioprotective agent according to the present invention containing a cyclic and / or chain-like polylactic acid mixture having a condensation degree of 3 to 19 as an active ingredient has a radioprotective effect against whole-body irradiation of radiation when administered before irradiation. Is shown.
- the polylactic acid mixture used as an active ingredient in the present invention is a low condensate of lactic acid derived from a biological component, and therefore has high biocompatibility and has few side effects.
Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU15543/01A AU1554301A (en) | 1999-12-03 | 2000-11-29 | Radioprotecting agent |
CA002393193A CA2393193A1 (fr) | 1999-12-03 | 2000-11-29 | Agent de protection contre le rayonnement |
EP00978007A EP1234577A1 (fr) | 1999-12-03 | 2000-11-29 | Agent de radioprotection |
KR1020027007060A KR20020069202A (ko) | 1999-12-03 | 2000-11-29 | 방사선 방호제 |
HK02108852.8A HK1047241A1 (zh) | 1999-12-03 | 2002-12-05 | 放射線防護劑 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP34404399 | 1999-12-03 | ||
JP11/344043 | 1999-12-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001039782A1 true WO2001039782A1 (fr) | 2001-06-07 |
Family
ID=18366228
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/008423 WO2001039782A1 (fr) | 1999-12-03 | 2000-11-29 | Agent de radioprotection |
Country Status (8)
Country | Link |
---|---|
US (1) | US20030072735A1 (fr) |
EP (1) | EP1234577A1 (fr) |
KR (1) | KR20020069202A (fr) |
CN (1) | CN1433315A (fr) |
AU (1) | AU1554301A (fr) |
CA (1) | CA2393193A1 (fr) |
HK (1) | HK1047241A1 (fr) |
WO (1) | WO2001039782A1 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002055091A1 (fr) * | 2001-01-12 | 2002-07-18 | Amato Pharmaceutical Products,Ltd. | Agents antiallergiques |
WO2002055092A1 (fr) * | 2001-01-16 | 2002-07-18 | Amato Pharmaceutical Products,Ltd. | Traitements preventifs et/ou remedes contre les maladies digestives |
WO2002055090A1 (fr) * | 2001-01-12 | 2002-07-18 | Amato Pharmaceutical Products,Ltd. | Agents preventifs d'infections microbiennes |
WO2002060457A1 (fr) * | 2001-01-24 | 2002-08-08 | Amato Pharmaceutical Products,Ltd. | Agents anti-stress |
WO2003007937A1 (fr) * | 2001-07-18 | 2003-01-30 | Amato Pharmaceutical Products, Ltd. | Agent antitumoral contenant de l'acide polylactique cyclique |
US6861538B1 (en) | 1999-09-20 | 2005-03-01 | Amato Pharmaceutical Products, Ltd. | Process for the preparation of cyclic lactic acid oligomer |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2881301A (en) * | 2000-01-26 | 2001-08-07 | Amato Pharmaceutical Products, Ltd. | Cancer cell implantation inhibitors |
JP2002265420A (ja) * | 2001-03-13 | 2002-09-18 | Tendou Seiyaku Kk | 鎖状オリゴ乳酸エステル |
TW200303299A (en) * | 2002-02-19 | 2003-09-01 | Amato Pharm Prod Ltd | Chain oligolactic acid thioester |
JPWO2003105869A1 (ja) * | 2002-06-12 | 2005-10-13 | 天藤製薬株式会社 | 抗癌剤副作用抑制剤 |
KR100791100B1 (ko) | 2007-01-05 | 2008-01-04 | 제주대학교 산학협력단 | 푸코이단을 유효성분으로 함유하는 방사선 방호용 조성물 |
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- 2000-11-29 EP EP00978007A patent/EP1234577A1/fr not_active Withdrawn
- 2000-11-29 AU AU15543/01A patent/AU1554301A/en not_active Abandoned
- 2000-11-29 CA CA002393193A patent/CA2393193A1/fr not_active Abandoned
- 2000-11-29 KR KR1020027007060A patent/KR20020069202A/ko not_active Application Discontinuation
- 2000-11-29 CN CN00818702A patent/CN1433315A/zh active Pending
- 2000-11-29 US US10/130,300 patent/US20030072735A1/en not_active Abandoned
- 2000-11-29 WO PCT/JP2000/008423 patent/WO2001039782A1/fr not_active Application Discontinuation
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2002
- 2002-12-05 HK HK02108852.8A patent/HK1047241A1/zh unknown
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JPH05310581A (ja) * | 1992-05-15 | 1993-11-22 | Koken Kk | 人を含む動物の悪性腫瘍細胞増殖抑制剤 |
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Publication number | Priority date | Publication date | Assignee | Title |
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US6861538B1 (en) | 1999-09-20 | 2005-03-01 | Amato Pharmaceutical Products, Ltd. | Process for the preparation of cyclic lactic acid oligomer |
WO2002055091A1 (fr) * | 2001-01-12 | 2002-07-18 | Amato Pharmaceutical Products,Ltd. | Agents antiallergiques |
WO2002055090A1 (fr) * | 2001-01-12 | 2002-07-18 | Amato Pharmaceutical Products,Ltd. | Agents preventifs d'infections microbiennes |
WO2002055092A1 (fr) * | 2001-01-16 | 2002-07-18 | Amato Pharmaceutical Products,Ltd. | Traitements preventifs et/ou remedes contre les maladies digestives |
WO2002060457A1 (fr) * | 2001-01-24 | 2002-08-08 | Amato Pharmaceutical Products,Ltd. | Agents anti-stress |
WO2003007937A1 (fr) * | 2001-07-18 | 2003-01-30 | Amato Pharmaceutical Products, Ltd. | Agent antitumoral contenant de l'acide polylactique cyclique |
Also Published As
Publication number | Publication date |
---|---|
KR20020069202A (ko) | 2002-08-29 |
HK1047241A1 (zh) | 2003-02-14 |
CN1433315A (zh) | 2003-07-30 |
EP1234577A1 (fr) | 2002-08-28 |
US20030072735A1 (en) | 2003-04-17 |
CA2393193A1 (fr) | 2001-06-07 |
AU1554301A (en) | 2001-06-12 |
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